Wang P, Gallagher K P, Downey J M, Cohen M V
Department of Physiology, University of South Alabama, Móbile 36688, USA.
J Mol Cell Cardiol. 1996 Mar;28(3):579-88. doi: 10.1006/jmcc.1996.0054.
We have proposed that ischemic preconditioning in rabbit hearts is initiated by adenosine receptor stimulation resulting in activation of protein kinase C. If this theory is correct then any agonist which can activate PKC should also put the heart into a preconditioned state. This study sought to determine whether endothelin-1 (ET-1), which is known to activate protein kinase C can also mimic ischemic preconditioning. Isolated rabbit hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.3 +/- 2.5% of the risk zone. Preconditioning with 5 min global ischemia and 10 min reperfusion reduced infarct size to 5.6 +/- 0.7% (P < 0.01). Perfusion with either 10 PM ET-1 at constant coronary artery flow for 5 min in lieu of ischemia or 50 PM ET-1 with 10 nM nicardipine to block the former's coronary constructive effect was quite protective and equipotent with preconditioning. Infarction averaged 7.2 +/- 0.8% and 5.8 +/- 1.7% of the risk zone, respectively. This protection could be blocked by PD 156 707 (10 microM), a highly specific endothelin receptor antagonist. Chelerythrine (5 microM), a PKC inhibitor, also aborted protection (22.0 +/- 1.7% infarction). However, 8-(p-sulfophenyl)theophylline (100 microM), an adenosine receptor blocker, given during ET-1 administration did not block ET-1's protective effect indicating that adenosine was not involved in the effect. PD 156707 failed to block the protection from ischemic preconditioning (12.6 +/- 2.3% infarction) revealing that endothelin is not an important physiological mediator of ischemic preconditioning. We conclude that ET-1 can mimic ischemic preconditioning in isolated rabbit hearts as would be predicted since its receptors are PKC-coupled, but that endogenous endothelin contributes little to ischemic preconditioning.
我们曾提出，兔心脏的缺血预处理是由腺苷受体刺激引发的，进而导致蛋白激酶C的激活。如果这一理论正确，那么任何能够激活蛋白激酶C的激动剂也应能使心脏进入预处理状态。本研究旨在确定已知可激活蛋白激酶C的内皮素-1（ET-1）是否也能模拟缺血预处理。离体兔心脏经历30分钟的局部缺血，随后再灌注120分钟。用氯化三苯基四氮唑测定梗死面积。在对照心脏中，梗死面积为危险区的30.3±2.5%。用5分钟全心缺血和10分钟再灌注进行预处理可将梗死面积降至5.6±0.7%（P<0.01）。在恒定冠状动脉血流条件下用10 pM ET-1灌注5分钟以替代缺血，或用50 pM ET-1加10 nM尼卡地平以阻断前者的冠状动脉收缩效应，均具有相当的保护作用且与预处理等效。梗死面积分别平均为危险区的7.2±0.8%和5.8±1.7%。这种保护作用可被高度特异性的内皮素受体拮抗剂PD 156 707（10 μM）阻断。蛋白激酶C抑制剂白屈菜红碱（5 μM）也可消除保护作用（梗死面积为22.0±1.7%）。然而，在给予ET-1期间给予腺苷受体阻断剂8-（对-磺基苯基）茶碱（100 μM）并未阻断ET-1的保护作用，表明腺苷不参与该效应。PD 156707未能阻断缺血预处理的保护作用（梗死面积为12.6±2.3%），揭示内皮素并非缺血预处理的重要生理介质。我们得出结论，ET-1能够在离体兔心脏中模拟缺血预处理，这正如所预期的，因为其受体与蛋白激酶C偶联，但内源性内皮素对缺血预处理的贡献很小。
